Duchenne and Becker Muscular Dystrophy — Dystrophin, Gowers Sign, Diagnosis and Management

Duchenne muscular dystrophy (DMD) is the most common hereditary neuromuscular disease of childhood and one of the most severe inherited muscular dystrophies. Mutations in the dystrophin gene cause progressive degeneration of muscle fibres, so a boy who was apparently normal in the first years of life becomes steadily weaker, loses the ability to walk, and usually dies in the twenties from respiratory muscle weakness or cardiomyopathy.

Becker muscular dystrophy (BMD) is an X-linked recessive disorder of the same gene. StatPearls calls it a milder form of DMD rather than a distinct clinical entity: symptoms appear later (anywhere from 5 to 60 years), progression is slower and many patients stay ambulant into adult life. Between the two lies an intermediate form with dystrophin levels between DMD and BMD. Together they are called the dystrophinopathies.

The dystrophin gene sits on the short arm of the X chromosome at Xp21. It is one of the largest genes in the human genome: 79 exons, about 2.5 Mb of DNA, coding a 427 kDa protein. Because the gene is so large, spontaneous mutation is common — roughly 30% of DMD cases are new mutations, with no family history. Most mutations are deletions or duplications (70–80%); point mutations account for 20–30%.

Dystrophin is a cytoskeletal protein that links actin inside the muscle fibre to the extracellular matrix through the dystrophin–glycoprotein complex (DGC). It is expressed in skeletal and cardiac muscle and, at lower levels, in brain and retina. Without it the sarcolemma becomes fragile and leaky: calcium homeostasis is disturbed, creatine kinase leaks out of the fibre, and repeated cycles of necrosis and regeneration eventually exhaust the muscle, which is replaced by fibrous and fatty tissue.

Carrier females are usually clinically normal, but about 2.5–20% of them become symptomatic. The explanation is the Lyon hypothesis: if the X chromosome carrying the normal gene happens to be inactivated in most cells (skewed X-inactivation), the mutant allele is expressed. Symptomatic carriers are also seen with Turner syndrome (45,X) or balanced X–autosome translocations that break the dystrophin gene.

Early development is usually normal or only slightly delayed, although growth velocity is slower and mild hypotonia or poor head control may be the first sign in infancy. The weakness that brings the child to the doctor appears between 2 and 3 years: toe walking, difficulty running and climbing stairs, and frequent falls. The weakness is proximal more than distal and lower limb more than upper limb.

Reflexes are reduced: knee jerks are less brisk than ankle jerks and may be lost by about 6 years, while ankle reflexes persist until late unless contractures develop. Patients typically become wheelchair-dependent by about 12 years. Pharyngeal weakness can cause aspiration, nasal regurgitation and a nasal voice. Sphincter incontinence is uncommon and is a late finding.

Cardiomyopathy is the major cause of death alongside respiratory failure. Symptoms can begin in the early teens and nearly every patient has cardiac involvement by the twenties. The pathology is dilated cardiomyopathy with fibrosis of the posterobasal left ventricular wall, which can spread to the lateral free wall; involvement of the posterior papillary muscle can produce mitral regurgitation. Intra-atrial conduction defects and supraventricular arrhythmias are more common than AV-nodal block. Persistent tachycardia or heart failure may be the first cardiac sign.

• ECG: tall R waves in V1–V6 with an increased R/S ratio and deep Q waves in leads I, aVL and V5–V6.
• Respiratory: scoliosis and weak respiratory muscles reduce vital capacity; pulmonary function should be tested before the child becomes wheelchair-bound and then twice a year once at 12 years or when vital capacity falls below 80% of predicted.
• Orthopaedic: contractures of ankles, knees, hips and elbows; falls cause fractures; steroid therapy adds the risk of osteoporosis.
• Anaesthesia: malignant hyperthermia after anaesthesia can, rarely, be the presenting event.

Suspect the diagnosis in a boy with proximal weakness, a characteristic examination and a family history. The work-up is serum CK, genetic testing and, when genetics is unhelpful, muscle biopsy, with an ECG and echocardiogram to look for cardiomyopathy.

In Becker muscular dystrophy, CK peaks later (about 10–15 years) and is also markedly raised. Because invasive biopsy is avoided where possible, genetic analysis, most often MLPA, is the first confirmatory test; dystrophin antibody staining on biopsy is kept for when the genetic result is negative. Muscle MRI in dystrophinopathies characteristically shows involvement of the gluteal muscles and adductor magnus with sparing of sartorius and gracilis.

There is no cure. Treatment centres on glucocorticoids, physiotherapy to prevent contractures, and active cardiac and respiratory care delivered by a multidisciplinary team. Glucocorticoids slow myofibre necrosis; in StatPearls' summary they are associated with better lung function, later scoliosis, less cardiomyopathy and improved survival.

Exercise should be gentle (swimming-pool and recreational activity) to avoid disuse atrophy; activity is reduced if myoglobinuria or severe muscle pain develops. For Becker muscular dystrophy there is no approved disease-specific drug; management mirrors milder DMD, with corticosteroids for significant weakness, ACE inhibitors with or without beta-blockers for cardiomyopathy, and rehabilitation. The steroid-like agent vamorolone is under study in BMD.

For related X-linked and inherited-pattern questions see Mendelian inheritance patterns; for steroid pharmacology revise corticosteroids.